scholarly journals Upregulation of CD3ζ and L‐selectin in antigen‐specific cytotoxic T lymphocytes by eliminating myeloid‐derived suppressor cells with doxorubicin to improve killing efficacy of neuroblastoma cells in vitro

2021 ◽  
Author(s):  
Weili Xu ◽  
Suolin Li ◽  
Meng Li ◽  
Hui Zhou ◽  
Xiaofeng Yang
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Neuroblastoma Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Cells in bone marrow and in T cell colonies grown from bone marrow can suppress generation of cytotoxic T lymphocytes directed against their self antigens.

1980 ◽  
Vol 152 (1) ◽  
pp. 54-71 ◽  
Author(s):  
S Muraoka ◽  
R G Miller
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic Activity ◽  
Cytotoxic T Lymphocytes ◽  
Suppressor Cells ◽  
Mouse Bone Marrow ◽  
Cytotoxic Lymphocyte ◽  
Radiation Resistant

Both normal mouse bone marrow and cells from T cell-containing colonies grown in vitro from normal bone marrow contain cells which can specifically suppress the development of cytotoxic T lymphocytes capable of recognizing alloantigens on the bone marrow or colony cells. Suppression, as assessed by reduction in cytotoxic activity, is produced by adding bone marrow or colony cells to mixed lymphocyte reactions between lymph node responder cells and irradiated histoincompatible spleen stimulator cells. The cytotoxic activity is reduced if the added bone marrow or colony cells are syngeneic or semisyngeneic to the stimulator cells but not if they are allogeneic. Suppression results from a reduction in the number of cytotoxic lymphocyte precursor cells activated in the cultures. The suppressor cells in bone marrow are radiation sensitive and Thy-1 negative; those in colonies grown from bone marrow are radiation resistant and Thy-1 positive.

Myeloid-Derived Suppressor Cells Increase in Chronic Myeloid Leukemia and Exert Immune Suppressive Activity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2779-2779
Author(s):  
Cesarina Giallongo ◽  
Nunziatina Parrinello ◽  
Daniele Tibullo ◽  
Piera La Cava ◽  
Alessandra Cupri ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Enzymatic Activity ◽  
Myeloid Leukemia ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1

Abstract Abstract 2779 Background: Tumor cells are able to develop immune evasion mechanisms which induce a state of immune tolerance and inactivate tumor-specific T cells. In this context, in some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. Aim: The aim of this study was to analyze MDSCs and investigate their involvement in T-cell anergy of CML patients. Methods: MDSCs were analyzed in peripheral blood (PB) of 13 CML patients (at diagnosis and during therapy) and healthy donors (HD; n=20) by cytofluorimetric analysis (CD14+DR- for monocytic MDSCs and CD11b+CD33+CD14-DR- for granulocytic MDSCs). Arginase 1 expression was assessed in PB of HD and CML patient using real time PCR. Purification of granulocytes, monocytes and lymphocytes from PB was performed by a positive magnetic separation kit (EasySep, STEMCELL Technologies). Arginase activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. To evaluate the activation of CD3+ T lymphocytes after incubation with phytoemagglutinin, we analyzed at 24, 48, 72 h the following markers: CD69+, CD71+, DR+. Microvesicles were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results: CML patients showed high levels of monocytic and granulocytic MDSCs at diagnosis in comparison to HD (63±8 and 83±12,2% respectively in CML vs 4,9±2,1 and 55,8±5,3% respectively in HD; p<0.001) while after 3–6 months of tyrosine kinase inhibitors (TKIs) therapy MDSC levels returned to normal values. Either in PB and in the purified granulocytes subpopulation, arginase1 expression showed a 30 fold increase in CML at diagnosis (CML vs HD: p<0.01) and decreased after therapy. We also evaluated arginase enzymatic activity in granulocytes and we found it increased in CML patients (n=4) compared to HD (n=5) (p<0.05). CML as well as HD T lymphocytes showed a normal activation in vitro which was significantly lost when they was incubated with CML serum (n=4). In addition, an increase of monocytic MDSCs in vitro was observed after incubation of HD monocytes with CML serum (39±6%; p<0.01) or microvescicles (9,2±1,2%; p<0.05) compared to control serum. Conclusions: Granulocytic and monocytic MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. Their levels also correlates with Arginase 1 expression and enzymatic activity in granulocytes. CML serum as well as CML microvesicles increase the percentage of HD monocytic MDSCs. Moreover, CML serum leads to anergy of T lymphocytes, probably by Arginase 1 secretion. Disclosures: Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

Anti-Tumor Activities of XBP1 Antigen-Specific Cytotoxic T Lymphocytes Are Enhanced By HDAC6 Inhibitor ACY241

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2143-2143
Author(s):  
Jooeun Bae ◽  
Matthew Ho ◽  
Brandon Nguyen ◽  
Arghya Ray ◽  
Dharminder Chauhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Board Of Directors ◽  
Cytotoxic T Lymphocytes ◽  
Cytokine Production ◽  
Suppressor Cells ◽  
Advisory Committees ◽  
Hdac6 Inhibitor ◽  
Equity Ownership

Abstract The effects of histone deacetylase (HDAC) inhibition on immune effector cells may have significant clinical implications; however, this has not yet been elucidated. The goal of this study was to investigate the immunomodulatory potential of the selective HDAC6 inhibitor ACY241 in combination with a cancer vaccine to enhance the efficacy of antigen-specific cytotoxic T lymphocytes (CTL) and the specific activities against tumor cells. Here, we report the effects of ACY241 treatment on antigen expression, immune activation, proliferation, and functional activities of XBP1 antigen-specific cytotoxic T lymphocytes (XBP1-CTL). The antigen-specific CTL were generated in vitro by repeated stimulation with novel immunogenic heteroclitic HLA-A2 XBP1 peptides (YISPWILAV, YLFPQLISV), as described previously by our group (Bae et al. Leukemia 2011; Bae et al. Oncoimmunology 2014l; Bae et al. Leukemia 2016). We found that treatment with ACY241 up-regulated key co-stimulatory (CD28, CD40L) and activation (CD38, CD69, CD137) molecules on XBP1-CTL, without inducing expression of co-inhibitory checkpoints (PD1, LAG3, CTLA4, VISTA). In addition, ACY241 increased the frequency of memory CTL subsets and enhanced their anti-tumor activities (cytotoxic activity, Th1-type cytokine production, CTL proliferation) against HLA-A2+ and XBP1+ multiple myeloma, breast cancer, and colon cancer cells. The XBP1-CTL responses were dramatically increased in combination with ACY241, including higher levels of tumor-specific CD107a up-regulation, perforin release, IFN-g/IL-2/TNF-a cytokine production and proliferation of the CD3+CD8+ T cells expressing CD28/CD38 in response to the specific XBP1 peptides. ACY241 also enhanced the expression of various tumor-associated antigens (XBP1, CD138, CS1, BCMA, CD44), MHC class I/II molecules, along with co-stimulatory B7 molecules (CD80, CD86) on HLA-A2+ myeloma (U266), breast cancer (MDA-MB231) and colon cancer (SW480) cell lines. Furthermore, in vitro ACY241 treatment consistently decreased the frequency of immune suppressor cells including myeloid-derived suppressor cells (CD14- CD15+/CD11b+ CD33+/HLA-DRlow) and regulatory T cells (CD25+ FOXP3+/CD3+ CD4+) in peripheral blood or bone marrow mononuclear cells from multiple myeloma patients in a dose-dependent manner. In conclusion, our data demonstrates the immunomodulatory effects of selective HDAC6 inhibition by ACY241 and supports its potential role for improving tumor-specific CTL function and tumor cell recognition when used in combination with antigen-specific cancer vaccine. Disclosures Bae: OncoPep Inc.: Consultancy, Equity Ownership. Chauhan:Stemline Therapeutics: Consultancy. Hideshima:Acetylon: Consultancy; C4 Therapeutics: Equity Ownership. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Anderson:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Cyclophosphamide-sensitive T lymphocytes suppress the in vivo generation of antigen-specific cytotoxic T lymphocytes

1977 ◽  
Vol 145 (2) ◽  
pp. 455-459 ◽  
Author(s):  
M Rollinghoff ◽  
A Starzinski-Powitz ◽  
K Pfizenmaier ◽  
H Wagner
Keyword(s):  
T Cells ◽  
Single Dose ◽  
T Lymphocytes ◽  
Cytotoxic Activity ◽  
Cytotoxic T Lymphocytes ◽  
Suppressor Cells ◽  
High Responsiveness ◽  
In Vivo Differentiation

Murine T lymphocytes sensitized in vitro against either allogeneic lymphocytes or syngeneic hapten-conjugated lymphocytes do differentiate into highly effective cytotoxic T lymphocytes (CTL) (1-3). In vivo immunization of T lymphocytes to the same antigens, however, results in the generation of only marginal cytotoxic activity (1,4,5). Recently we found that the weakness of in vivo generated cytotoxicity is not due to a failure of antigen-induced T-cell sensitization but rather due to suppression of the in vivo differentiation of sensitized CTL precursors into effective CTL(6). In keeping with this finding it was postulated that suppressor cells may regulate the in vivo differentiation of CTL. We now report, that cyclophosphamide-sensitive T cells suppress the in vivo differentiation of antigen-specific CTL. Thus, pretreatment of mice with a single dose of cyclophosphamide (100 mg/kg) converts their state of low responsiveness to a state of high responsiveness.

755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A803-A803 ◽  
Author(s):  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Itziar Migueliz ◽  
Assunta Cirella ◽  
Ignacio Melero
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Suppressor Cells ◽  
Neutrophil Extracellular Traps ◽  
Myeloid Derived Suppressor Cells ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

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